Analysis of the structural databank indicates that the overwhelming majority of protein structures can be classified as belonging to one of a very limited number of fundamental protein architectures (currently comprising ten such “superfolds”). These architectures represent a kinetic and thermodynamic solution to the protein folding problem, and their limited number suggests that the evolution of functionality within the proteome is achieved primarily through modification of existing protein architectures, rather than entirely new designs. Experimental and theoretical studies of protein stability and function relationships suggest that novel functionality is typically achieved at the expense of stability (i.e. the “stability/function tradeoff” hypothesis). Together, these results additionally suggest that an important property of the ten fundamental superfolds is the ability to accommodate a wide variety of mutations, yet remain stably folded. Thus, the ten fundamental protein architectures likely share a basic property, namely, the potential for substantial thermodynamic stability.
The majority of the fundamental superfolds exhibit some form of tertiary structure symmetry, the postulated result of gene duplication and fusion events during the evolutionary process. Despite this tertiary structure symmetry, such proteins may exhibit little if any related primary structure symmetry, indicating substantial divergence must have occurred following the presumed ancient gene duplication/fusion events. Based upon the stability/function trade-off hypothesis, some fraction of the observed divergence is associated with the emergence of novel functionalities, but at the expense of stability. This leads to the intriguing hypothesis that it may be possible to redesign a protein, belonging to a symmetric superfold, by enforcing a symmetric primary structure constraint, and yet, have the resulting mutant protein increase thermodynamic stability. Such design solutions would have obvious importance in elucidating the process of protein evolution, and also have practical applications in de novo protein design.